A critical goal in prostate cancer (PC) epidemiology is identifying the biological mechanism underlying the progression from clinically non- significant PC to clinically relevant PC. We propose to conduct a case- case study comparing a group of 100 men with non-significant PC and an age- and ethnic-matched group of 300 men with clinically relevant PC. These two groups will be characterized by comprehensive epidemiologic profiles and by comparison of multiple genetic alterations in their PC lesions. The objective is to identify environmental and genetic determinants of PC progression. The long term goal is to identify and clone a tumor suppressor gene (rSG), frequently inactivated in PC, that might be a future target for therapy. The hypothesis being tested is that foci of preneoplasia or low grade cancer have experienced some, but not all, the necessary steps to progress to invasive cancer, and that environmental and genetic factors play a role in this progression. The epidemiologic component will compare risk profiles of men with respect to previously reported and putative risk factors (including dietary intake of total fat, fatty acids, and micronutrients, sociodemographic factors, patterns of body fat distribution, vasectomy, family history and male patterns of balding). The working hypotheses are that environmental factors play a role in the development of the aggressive phenotype. The molecular genetic component will focus on analysis of allele loss in the two groups of men by screening all available paired specimens of PC and normal tissues and/or preneoplastic lesions such as prostatic intraepithelial neoplasia. The working hypothesis is that frequent LOH at specific chromosomal regions,which is associated with inactivation of tumor suppressor genes, is a major mechanism in the progression of PC and that non-significant PC can be distinguished from clinical PC on the basis of genetic changes. Our goal is to identify new molecular genetic markers, highly associated with the progression of PC, and that can be used as diagnostic and prognostic markers. In addition, this component will focus on limiting chromosomal regions which show frequent LOH/deletions to a specific chromosomal band or sub-bands by generating new polymorphic microsatellite probes from microdissected chromosomal regions. The presence of lesions of unknown malignant potential poses a serious therapeutic dilemma. Environmental factors in concert with genetic alterations such as frequent LOH at specific chromosomal regions may be important mechanisms in the progression of PC and may be of predictive and therapeutic value.